Preparation of vitamin compositions



Potestedse t. 19,1944

' Purses-non or vrrssmz COMPOSITIONS Elmer J. Lawson and Hervey o. M... Detroit.

Mich, assiznors to Berke, Davis a Company. Detroit, Mich, acorporation of Michigan.

Serial No. 407,358

- No Drawing. Application mm 1a, 1941,

Claims. ((31. 260-434) This invention relates to vitamin compositions and their preparation. More particularly; this invention relates to the preparation of pantothenic acid, a vitamin of the-B complex occurring in liver and in yeast. Pantothenlc acid has the following structural formula,

on. on 0 and may be said to be the p-alanide of aJy-dihyis removed, and the'clear solution diluted with about 800 cc. of warm acetone. On cooling, the racemic sodium a -dihydroxy-pp-dimethylbutyrate crystallizes. It melts at 190 C. and is not hygroscopic.

B. 'A mixture of 1.70-g.'of racemic sodium a.-ydihydroxyApp-dimethylbutyrate and 0.89 g. of palanine is heated-to 175 C., at which point fusion droxy-B.Bdimethylbutyric acid. Pantothenic acid and its salts, almost all of which are very soluble in water, arecflective in stimulating the growth of yeast, bacteria and various other organisms.

It will be noticed that the carbon atom marked with an asterisk (l is asymmetric. Of the two enantiomorphous forms, only the dextrorotatory form isbiologically active.

This invention has for its object an improved process for the preparation of pantothenic acid and its derivatives.- I

According to our invention, we prepare salts of pantothenic acid by reacting p-alanine and a salt of a,-y-dihydroxy-p,p-dimethylbutyric acid at elevated temperatures, best in the neighborhood of 150-200 C. The saIts-of,a,'1-dlhY W-F.B dimethylbutyric acid are prepared by reacting ahydroXV-Bfi dimethyl v butyrolactonewith a strong base. We prefer to use the alkali or alkaline earth metal salts in this process thereby obtaining alkali or alkaline earth metal salts of ,'y-dihydroxy-p,p-dimethylbutyric acid. While the reaction of the p-alanine with the. salt of v-dihydroxy-ap-dimethylbutyric acid may be eflected by heating the two components .in the presence of a solvent such as ethylene glycol, quinoline. tetralin or other inert solvents, weprefer to conduct the reaction simply by fusing the two components in theabsence of any solvent.

Our invention may be further illustrated by the following examples: I

Example 1 takes place. The fusedmass is maintained at 150 C. for an hour and then allowed to cool in a desiccator. The glassy product may be assayed by the bacterial growth method; the activity corresponds to a 91% yield of moeimo sodium pantothenate.

Example 2 A. (as hydro fifi-dlmethyl-vsbutyrolac tone is obtained by resolution of the racemic lactone with quinine.

B. A solution of 13 g. 'of (-)a-hydroxy-p,p-

dimethyly-butyrolactone and 40 g. of barium hydroxide octahydrate in 200 cc. of water is refluxed for two hours, cooled, and the excess barium precipitated with a stream of carbon dibutyrate is prepared methanolic extracts are combined. concentrated to a volume of cc. and allowed to stand. The

filtered and the filtrate The residue of barium oxide. The mixture is evaporated to dryness.

(+) -o=;y-dihydroxy-p,p-dimethylbutyrate is purifled .by recrystallization from water-acetone. The salt has M. P. 213-215 C. and [al =+'l.4

' (C=5% in water) 0. Sodium -,-y-dihydroxy as 4 dimethylby mixing solutions of equivalent amounts of the bariumsalt above and sodium sulfate in aqueous solution. The precipitated barium sulfate is removed by filtration or ce'ntriiugin: andzthe clear liquor evaporated to dryness. The residue is dissolved in a small amount of methanol and crystallized by addition I of a large. excess ofacetone. vThe desired sodium salt may separate at ilrst as an oil, but it rapidly crystallizes and then may be cooled and purified by recrystallization from methanol acetone.

M. P. 99-101 (7., which is not hygroscopic. This form has thesame specific rotation as the higher melting form and is apparently an allotropic modification. Bothforms aredeflnitely crystalline as is readily seen by examining them under next morning the slight deposit which has formed 66 the polarizing (c -om in.

' 1A. Alternatively, it may hydroxy-flifl-dimethylbutyrate and-1.78 'g. or palanine is fused at 180' C. for 15 minutes and then cooled quickly. The resulting glass is sodium d-pantothenate. It may be purified by tractional precipitation from alcohol-ether solutions or by crystallization from absolute alcohol.

Example 3 p This is triturated with acetone and collected.

Thus, there is obtained racemic barium GfY-dihydroxy-pp-dimethylbutyrate monohydrate.

B. Racemic sodium a,-y-dihydroxy-p,,e-dimeth-' ylbutyrate may be prepared according to Example be prepared by mixin; hot aqueous solution 01' equimolar amounts of racemic barium a,-y-dihydroxy-p,p-dimethylbutyrate monohydrate and sodium sulfate, removing the barium suli'ate by nitration, evaporating the nitrate to dryness and crystallizing thefresidue from acetone-methanol.

C. A solution. 01' 0.85 g. of racemic sodium a,'ydihydroxy-ap-dlmethylbutyrata and 0.445 g. 01' alanine in 10 cc. of ethylene glycol is refluxed tor 20 minutes, alter which the glycol is removed by distillation under reduced pressure. The residue is racemic sodium pantothenate. Instead of using sodium an-dlhYdl'OXY-Pfi-dlmethylbutyrate in the above reaction, barium -p,p-dimethylbutyrate may be used I a,-y-dlhydroxy thereby obtaining racemic barium pantothenate.

assassin Example 4 A mixture or 1.124 g. of barium ary-dihydroxy- Ab-dimethylbutyrate and 0.445 g. or p-alanine is fused in an oil bath at 200 C. The temperature is allowed to drop slowly to 180 C. over a period 01' 15 minutes, after which the fused mixture is cooled andrulverized. This is racemic barium pantothenate.

What we claim as our invention is:

1. Process for preparing a salt of pantothenic acid which comprises reacting in non-aqueous phase substantially equivalent amounts o1 p-alanine and a salt'oi' wy-dihydroxy-mp-dimethylbutyric acid at 150-200 C.

2. Process for preparing a salt of pantothenic acid which comprises reacting in non-aqueous phase substantially equivalent amounts oi p-alanine and a member or the class consisting oi alkali metal a,-y-dihydroxy-p,p-dimethylbutyrates and alkaline earth metal a,' -dihydroxy-p,p-dimethylbutyrates at 150-200 C. v

8. Process for preparing rac'emic sodium pantothenate which comprises reacting in non-aqueous phase substantially equivalent amounts oi p-alanine and racemic sodium wy-dihydroxy-fip-dimethylbutyrate at 150-200 C.

4. Process for preparing sodium d-pantothen-.

ate which comprises reacting in. non-aqueous phase substantially equivalent amounts of ,e-alanine and sodium d-a,' -d1hydroxy-p,p-dimethylbutyrate at ISO-200 C.

5. Process for preparing sodium d-pantothenate which comprises fusing substantially equivalent amounts of p-alanine and sodium d-llfl-dl hydro y-flifl-dimethylbutyrate for approximately fifteen minutes at ITO-180 C.

ELMER J. LAWSON. mm c. PARKE. 

